Alkylamines are among the most common functional groups in pharmaceuticals. The hydroamination of alkenes is one of the simplest and most atom-economical methods to prepare alkylamines, and much effort has now been spent to develop catalysts for such additions of amines to alkenes.
One of the earliest reports of hydroamination was the hydroamination of ethylene with secondary amines, catalyzed by rhodium trichloride (Coulson, D. R. Tetrahedron Lett. 12, 429, 1971). A drawback to this approach is that the reaction has only been demonstrated with unsubstituted ethylene, and only when reacted at high temperatures. Most research has been focused on hydroamination of substituted alkenes at temperatures below 100° C.
One approach to hydroamination has been to use activated alkenes. Examples of activated alkenes include alkenes in strained ring systems, such as norbornenes, which have been subjected to hydroamination catalyzed by complexes of transition metals such as iridium (A. L. Casalnuovo et al. J. Am. Chem. Soc. 110, 6738, 1988; R. Dorta et al. J. Am. Chem. Soc. 119, 10857, 1997). Examples of activated alkenes also include vinyl arenes, which have been subjected to hydroamination catalyzed by complexes of transition metals such as rhodium (Beller, M. et al. Eur. J. Inorg. Chem. 1121, 1999; Beller, M. et al. Chem. Eur. J. 5, 1306, 1999). Examples of activated alkenes also include allenes, which have been subjected to hydroamination catalyzed by complexes of transition metals such as titanium (Walsh, P. J. et al. J. Am. Chem. Soc. 114, 1708, 1992; Johnson, J. S. et al. J. Am. Chem. Soc. 123, 2923, 2001.). These reactions have met with mixed success.
Activated alkenes such as vinyl arenes, 1,3-dienes, acrylates and acrylonitriles have been subjected to hydroamination catalyzed by complexes of transition metals such as iron, cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium, and platinum (Kawatsura, M. et al. J. Am. Chem. Soc. 122, 9546, 2000; O. Löber et al. J. Am. Chem. Soc. 123, 4366, 2001; Utsunomiya, M. et al. J. Am. Chem. Soc. 125, 5608, 2003; Utsunomiya, M. et al. J. Am. Chem. Soc. 126, 2702, 2004; Takemiya, A. et al. J. Am. Chem. Soc. 128, 6042, 2006). In many cases, these reactions could be performed at room temperature with high yields. Enantioselectivity also could be observed for some systems. A drawback to this approach is that the reactants have included either a vinyl arene or an aromatic amine. Thus, simple alkylamine products have not been reported. Also, hydroamination has been reported only for activated alkenes, in which one carbon of the carbon-carbon double bond was bonded to a sp2 hybridized carbon, such as a ring carbon of an aromatic ring, a carbon of another carbon-carbon double bond, a carbonyl carbon (>C═O), or a carbon of a cyano group. The need for an activated alkene limits the scope of substrates that can be used.
Another approach to hydroamination has been to use activated nitrogen sources, instead of amines. Activated nitrogen sources such as sulfonamides, amides and carbamates have been added to vinylarenes, allenes and alkenes. These reactions have been catalyzed by late transition metals, such as iron, palladium, platinum, copper and gold, as well as by protic acids. A drawback to these reactions is that the products do not include simple amino groups, and thus are not alkylamines.
Yet another approach to hydroamination has employed catalytic complexes of lanthanides, actinides, or group IV transition metals such as titanium or zirconium. These catalysts can be highly efficient, and can be used for hydroamination of unactivated alkenes. However, a drawback to this approach is that the catalysts are highly sensitive to air and moisture, and do not have good tolerance of functional groups. Thus, these reactions have not been used widely in the synthesis of complex organic molecules.
It would be desirable to transform unactivated alkenes into alkylamines in a way that is relatively insensitive to air and moisture. It would also be desirable to provide alkylamines from substrates that include one or more functional groups in addition to the alkene group. Ideally, such a system would provide alkylamines from terminal or internal alkenes, using primary or secondary amino groups.